Savara Inc. is developing a novel inhaled dry-powder form of vancomycin (AEROVANC) for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infection, initially in cystic fibrosis (CF) patients and subsequently in other high risk patient populations. The product is intended for convenient self-administration at home. It is envisioned to improve lung function, as well as, to decrease hospitalization rates and use of intravenous (IV) antibiotics. MRSA infections have become increasingly common, with a prevalence of up to 40-50% of all CF patients1; and are associated with an average of 6.2 years shorter life-expectancy compared to CF patients without MRSA. Vancomycin is the drug of choice for the treatment of bronchopneumonia due to MRSA, but it is only available in IV form. Vancomycin is also associated with systemic toxicity, generally, limiting its use to hospital settings. There is significant clinical advantage in delivering vancomycin directly to the site of infection in order to reduce systemic exposure. The off-label administration of the IV product has proven to be encouraging. The published data from clinical trials4-11 indicate that pulmonary administration of vancomycin is safe and well tolerated, and reduces or eliminates MRSA from the sputum of CF patients suffering from MRSA lung infections. However, the IV formulation has not been optimized for pulmonary administration. There are considerable technical challenges and limitations to its use that have not been adequately addressed, and that impact its clinical viability. Savara has overcome the significant technical challenges to the development of an inhalable vancomycin powder by using innovative particle coating technology, enabling for the first time the development of a practical and effective inhalation treatment of pulmonary MRSA infection. Savara's novel dry-powder formulation of vancomycin (AEROVANC) has physical, chemical and aerodynamic properties suitable for delivery using off-the-shelf inhaler devices. The product is in preclinical development. This SBIR grant focuses on two lines of investigation. The first is directed at CMC- related activities, i.e., translating the laboratory-scale formulatio into a formulation and manufacturing process capable of supporting IND and clinical investigation. Savara will scale-up the formulation using equipment suitable for cGMP manufacture, at a scale suitable for completion of the preclinical program and Phase I clinical studies. The second line of study is directed at establishing the safety and maximum tolerated dose (MTD) of AEROVANC and characterizing its pharmacokinetic profile in the lung and in blood. A single dose, dose-escalation study will be carried out in which the AEROVANC formulation will be administered by inhalation to healthy rats. Acute toxicology profiles will be determined and end-organ toxicities will be identified by clinical observation and gross necropsy. Serial samples of both lung fluid and blood will be drawn, analyzed for vancomycin levels and used to establish pharmacokinetic profiles. The completion of the work proposed by the Phase 1 SBIR will position Savara to initiate GLP activities and pre-IND discussions with FDA. PUBLIC HEALTH RELEVANCE: The most common cause of death among cystic fibrosis (CF) patients is respiratory failure secondary to chronic pulmonary infections, including methicillin-resistant Staphylococcus aureus (MRSA) infections, which are prevalent in 40-50% of CF patients, and have been shown to be associated with a shorter life expectancy compared to CF patients without MRSA. Vancomycin, the drug of choice for the treatment of bronchopneumonia due to MRSA, is available only in intravenous form, and has severe toxicities that limit its use to expensive and inconvenient hospital administration. To address the documented need for additional therapies to address this condition, Savara Inc. is developing a much safer inhaled dry-powder form of vancomycin (AEROVANC) for the local treatment of MRSA infections, which is intended for convenient, low cost self-administration at home.